US9981939B2 - Compounds and uses thereof for the modulation of hemoglobin - Google Patents

Compounds and uses thereof for the modulation of hemoglobin Download PDF

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US9981939B2
US9981939B2 US14/776,603 US201414776603A US9981939B2 US 9981939 B2 US9981939 B2 US 9981939B2 US 201414776603 A US201414776603 A US 201414776603A US 9981939 B2 US9981939 B2 US 9981939B2
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mmol
alkyl
optionally substituted
mixture
solution
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US20160046613A1 (en
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Brian W. Metcalf
Zhe Li
Qing Xu
II Stephen L. Gwaltney
Jason R. Harris
Calvin W. YEE
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Global Blood Therapeutics Inc
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Global Blood Therapeutics Inc
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Priority claimed from US13/815,770 external-priority patent/US9422279B2/en
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Assigned to GLOBAL BLOOD THERAPEUTICS, INC. reassignment GLOBAL BLOOD THERAPEUTICS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GWALTNEY, STEPHEN L., II, YEE, Calvin W., HARRIS, JASON R., XU, QING, LI, ZHE, METCALF, BRIAN W.
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    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
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    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring

Definitions

  • This invention provides compounds and pharmaceutical compositions suitable as allosteric modulators of hemoglobin, methods and intermediates for their preparation, and methods for their use in treating disorders mediated by hemoglobin and disorders that would benefit from tissue and/or cellular oxygenation.
  • Sickle cell disease is a disorder of the red blood cells, found particularly among those of African and Mediterranean descent.
  • the basis for sickle cell disease is found in sickle hemoglobin (HbS), which contains a point mutation relative to the prevalent peptide sequence of hemoglobin (Hb).
  • Hemoglobin transports oxygen molecules from the lungs to various tissues and organs throughout the body. Hemoglobin binds and releases oxygen through conformational changes.
  • Sickle hemoglobin (HbS) contains a point mutation where glutamic acid is replaced with valine, allowing HbS to become susceptible to polymerization to give the HbS containing red blood cells their characteristic sickle shape. The sickled cells are also more rigid than normal red blood cells, and their lack of flexibility can lead to blockage of blood vessels.
  • U.S. Pat. No. 7,160,910 discloses compounds that are allosteric modulators of hemoglobin. However, a need exists for additional therapeutics that can treat disorders that are mediated by Hb or by abnormal Hb such as HbS.
  • This invention relates generally to compounds and pharmaceutical compositions suitable as allosteric modulators of hemoglobin. In some aspects, this invention relates to methods for treating disorders mediated by hemoglobin and disorders that would benefit from tissue and/or cellular oxygenation.
  • V 1 and V 2 together with the carbon atom they are attached to form a ring of formula:
  • V 1 and V 2 independently are C 1 -C 6 alkoxy; or V 1 and V 2 together with the carbon atom they are attached to form a ring of formula:
  • each V 3 and V 4 are independently O, S, or NH, provided that when one or V 3 and V 4 is S the other is NH, and provided that V 3 and V 4 are both not NH; q is 1 or 2; each V 5 is independently C 1 -C 6 alkyl or CO 2 R 60 , where each R 60 independently is C 1 -C 6 alkyl or hydrogen; t is 0, 1, 2, or 4; or CV 1 V 2 is C ⁇ V, wherein V is O, and wherein the remaining variables are defined herein.
  • composition comprising any of the compounds described herein, and at least a pharmaceutically acceptable excipient.
  • a method for increasing oxygen affinity of hemoglobin S in a subject comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or compositions described herein.
  • a method for treating oxygen deficiency associated with sickle cell anemia comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or compositions described herein.
  • compositions and methods are intended to mean that the compositions and methods include the recited elements, but not excluding others.
  • Consisting essentially of when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition or process consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed invention.
  • Consisting of shall mean excluding more than trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention.
  • C m -C n such as C 1 -C 12 , C 1 -C 8 , or C 1 -C 6 when used before a group refers to that group containing m to n carbon atoms.
  • alkoxy refers to —O-alkyl
  • alkyl refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 12 carbon atoms (i.e., C 1 -C 12 alkyl) or 1 to 8 carbon atoms (i.e., C 1 -C 8 alkyl), or 1 to 4 carbon atoms.
  • This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH 3 —), ethyl (CH 3 CH 2 —), n-propyl (CH 3 CH 2 CH 2 —), isopropyl ((CH 3 )CH—), n-butyl (CH 3 CH 2 CH 2 CH 2 —), isobutyl ((CH 3 ) 2 CHCH 2 —), sec-butyl ((CH 3 )(CH 3 CH 2 )CH—), t-butyl ((CH 3 ) 3 C—), n-pentyl (CH 3 CH 2 CH 2 CH 2 CH 2 —), and neopentyl ((CH 3 ) 3 CCH 2 —).
  • linear and branched hydrocarbyl groups such as methyl (CH 3 —), ethyl (CH 3 CH 2 —), n-propyl (CH 3 CH 2 CH 2 —), isopropyl ((CH 3 )CH—), n
  • aryl refers to a monovalent, aromatic mono- or bicyclic ring having 6-10 ring carbon atoms. Examples of aryl include phenyl and naphthyl. The condensed ring may or may not be aromatic provided that the point of attachment is at an aromatic carbon atom. For example, and without limitation, the following is an aryl group:
  • —CO 2 H ester refers to an ester formed between the —CO 2 H group and an alcohol, preferably an aliphatic alcohol.
  • chiral moiety refers to a moiety that is chiral. Such a moiety can possess one or more asymmetric centers. Preferably, the chiral moiety is enantiomerically enriched, and more preferably a single enantiomer.
  • Non limiting examples of chiral moieties include chiral carboxylic acids, chiral amines, chiral amino acids, such as the naturally occurring amino acids, chiral alcohols including chiral steroids, and the likes.
  • cycloalkyl refers to a monovalent, preferably saturated, hydrocarbyl mono-, bi-, or tricyclic ring having 3-12 ring carbon atoms. While cycloalkyl, refers preferably to saturated hydrocarbyl rings, as used herein, it also includes rings containing 1-2 carbon-carbon double bonds. Nonlimiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamentyl, and the like. The condensed rings may or may not be non-aromatic hydrocarbyl rings provided that the point of attachment is at a cycloalkyl carbon atom. For example, and without limitation, the following is a cycloalkyl group:
  • halo refers to F, Cl, Br, and/or I.
  • heteroaryl refers to a monovalent, aromatic mono-, bi-, or tricyclic ring having 2-16 ring carbon atoms and 1-8 ring heteroatoms selected preferably from N, O, S, and P and oxidized forms of N, S, and P, provided that the ring contains at least 5 ring atoms.
  • Nonlimiting examples of heteroaryl include furan, imidazole, oxadiazole, oxazole, pyridine, quinoline, and the like.
  • the condensed rings may or may not be a heteroatom containing aromatic ring provided that the point of attachment is a heteroaryl atom.
  • heterocyclyl refers to a non-aromatic, mono-, bi-, or tricyclic ring containing 2-12 ring carbon atoms and 1-8 ring heteroatoms selected preferably from N. O, S, and P and oxidized forms of N, S, and P, provided that the ring contains at least 3 ring atoms. While heterocyclyl preferably refers to saturated ring systems, it also includes ring systems containing 1-3 double bonds, provided that the ring is non-aromatic.
  • heterocyclyl examples include, azalactones, oxazoline, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl, and tetrahydropyranyl.
  • the condensed rings may or may not contain a non-aromatic heteroatom containing ring provided that the point of attachment is a heterocyclyl group.
  • the following is a heterocyclyl group:
  • hydrolyzing refers to breaking an R H —O—CO—, R H —O—CS—, or an R H —O—SO 2 — moiety to an R H —OH, preferably by adding water across the broken bond.
  • a hydrolyzing is performed using various methods well known to the skilled artisan, non limiting examples of which include acidic and basic hydrolysis.
  • oxo refers to a C ⁇ O group, and to a substitution of 2 geminal hydrogen atoms with a C ⁇ O group.
  • the group may be substituted with one or more substituents, such as e.g., 1, 2, 3, 4 or 5 substituents.
  • the substituents are selected from the group consisting of oxo, halo, —CN, NO 2 , —N 2 +, —CO 2 R 100 , —OR 100 , —S 100 , —SOR 100 , —SO 2 R 100 , —NR 101 R 102 , —CONR 101 R 102 , —SO 2 NR 101 R 102 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —CR 100 ⁇ C(R 100 ) 2 , —CCR 100 , C 3 -C 10 cycloalkyl, C 3 -C 10 heterocyclyl, C 6 -C 12 aryl and C 2 -C 12 heteroaryl, wherein each
  • the substituents are selected from the group consisting of chloro, fluoro, —OCH 3 , methyl, ethyl, iso-propyl, cyclopropyl, vinyl, ethynyl, —CO 2 H, —CO 2 CH 3 , —OCF 3 , —CF 3 and —OCHF 2 .
  • R 101 and R 102 independently is hydrogen; C 1 -C 8 alkyl, optionally substituted with —CO 2 H or an ester thereof, C 1 -C 6 alkoxy, oxo, —CR 103 ⁇ C(R 103 ) 2 , —CCR, C 3 -C 10 cycloalkyl, C 3 -C 10 heterocyclyl, C 6 -C 12 aryl, or C 2 -C 12 heteroaryl, wherein each R 103 independently is hydrogen or C 1 -C 8 alkyl; C 3 -C 12 cycloalkyl; C 3 -C 10 heterocyclyl; C 6 -C 12 aryl; or C 2 -C 12 heteroaryl; wherein each cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-3 alkyl groups or 1-3 halo groups, or R 101 and R 102 together with the nitrogen atom they are attached to form a 5-7 membered heterocycle.
  • pharmaceutically acceptable refers to safe and non-toxic for in vivo, preferably, human administration.
  • pharmaceutically acceptable salt refers to a salt that is pharmaceutically acceptable.
  • salt refers to an ionic compound formed between an acid and a base.
  • salts include, without limitation, alkali metal, alkaline earth metal, and ammonium salts.
  • ammonium salts include, salts containing protonated nitrogen bases and alkylated nitrogen bases.
  • Exemplary, and non-limiting cations useful in pharmaceutically acceptable salts include Na, K, Rb, Cs, NH 4 , Ca, Ba, imidazolium, and ammonium cations based on naturally occurring amino acids.
  • salts include, without limitation, salts of organic acids, such as carboxylic acids and sulfonic acids, and mineral acids, such as hydrogen halides, sulfuric acid, phosphoric acid, and the likes.
  • exemplary and non-limiting anions useful in pharmaceutically acceptable salts include oxalate, maleate, acetate, propionate, succinate, tartrate, chloride, sulfate, bisulfate, mono-, di-, and tribasic phosphate, mesylate, tosylate, and the likes.
  • treat include alleviating, abating or ameliorating a disease or condition or one or more symptoms thereof, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting or suppressing the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or suppressing the symptoms of the disease or condition, and are intended to include prophylaxis.
  • the terms also include relieving the disease or conditions, e.g., causing the regression of clinical symptoms.
  • the terms further include achieving a therapeutic benefit and/or a prophylactic benefit.
  • compositions are administered to an individual at risk of developing a particular disease, or to an individual reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.
  • preventing or “prevention” refer to a reduction in risk of acquiring a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease).
  • the terms further include causing the clinical symptoms not to develop, for example in a subject at risk of suffering from such a disease or disorder, thereby substantially averting onset of the disease or disorder.
  • an effective amount refers to an amount that is effective for the treatment of a condition or disorder by an intranasal administration of a compound or composition described herein.
  • an effective amount of any of the compositions or dosage forms described herein is the amount used to treat a disorder mediated by hemoglobin or a disorder that would benefit from tissue and/or cellular oxygenation of any of the compositions or dosage forms described herein to a subject in need thereof.
  • carrier refers to relatively nontoxic chemical compounds or agents that facilitate the incorporation of a compound into cells, e.g., red blood cells, or tissues.
  • a “prodrug” is a compound that, after administration, is metabolized or otherwise converted to an active or more active form with respect to at least one property.
  • a pharmaceutically active compound can be modified chemically to render it less active or inactive, but the chemical modification is such that an active form of the compound is generated by metabolic or other biological processes.
  • a prodrug may have, relative to the drug, altered metabolic stability or transport characteristics, fewer side effects or lower toxicity. For example, see the reference Nogrady, 1985, Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392.
  • Prodrugs can also be prepared using compounds that are not drugs.
  • V 1 and V 2 together with the carbon atom they are attached to form a ring of formula:
  • V 1 and V 2 independently are C 1 -C 6 alkoxy; or V 1 and V 2 together with the carbon atom they are attached to form a ring of formula:
  • each V 3 and V 4 are independently O, S, or NH, provided that when one or V 3 and V 4 is S the other is NH, and provided that V 3 and V 4 are both not NH; q is 1 or 2; each V is independently C 1 -C 6 alkyl or CO 2 R 60 , where each R 60 independently is C 1 -C 6 alkyl or hydrogen; t is 0, 1, 2, or 4; or CV 1 V 2 is C ⁇ V, wherein V is O, and wherein the remaining variables are defined herein.
  • t is 0. In certain embodiments, t is 1. In certain embodiments, t is 2. In certain embodiments, t is 3. In one embodiment, —X—Y— is —CH 2 —O—. In another embodiment, —X—Y is —O—CH 2 —.
  • ring A is
  • ring A is pyridyl, optionally substituted as defined herein.
  • a compound is provided, wherein the compound selected from the group consisting of:
  • a compound is provided, wherein the compound selected from the group consisting of:
  • a compound is provided, wherein the compound is selected from the group consisting of:
  • ring C is substituted with at least one substituent selected from with 1-4: halo, —OR 1 , C 1 -C 6 alkyl, —COOR 5 , NR 5 R 6 .
  • X is CH 2 , O, S, SO, SO 2 or NH. In certain embodiments. X is O, S, SO or SO 2 . Preferably, X is O, and wherein the remaining variables are defined herein.
  • Y is CR 20 R 21 , O, S. SO, SO 2 , or NR 10 ; wherein each R 20 and R 21 independently is hydrogen or C 1 -C 3 alkyl. In certain embodiments, Y is CR 20 R 21 wherein each R 20 and R 21 independently is hydrogen or C 1 -C 3 alkyl. Preferably, Y is CH 2 , and wherein the remaining variables are defined herein.
  • t is 0. In certain embodiments, t is 1. In certain embodiments, t is 2. In certain embodiments, t is 3.
  • CV 1 V 2 is C ⁇ V, wherein V is O, and wherein the remaining variables are defined herein.
  • R 4 is —OH. In another embodiment, R 4 is NH 2 . In one embodiment, R 4 is NH(CH 3 ). In one embodiment, R 4 is N(CH 3 ) 2 . In one embodiment, R 4 is NHC(O)OC(CH 3 ) 3 . In one embodiment, R 4 is COOH. In one embodiment, R 4 is optionally substituted dioxolan. In one embodiment, R 4 is a substituted pyridine. As used herein, R 1 is hydrogen, provided that the COOR 3 is not joined to a nitrogen atom.
  • ring B is selected from the group consisting of:
  • a compound is provided, wherein the compound is selected from the group consisting of:
  • R is hydrogen, a phosphate or a diphosphate containing moiety, or another promoiety or prodrug moiety.
  • the prodrug moiety imparts at least a 2 fold, more preferably a 4 fold, enhanced solubility and/or bioavailability to the active moiety (where R is hydrogen), and more preferably is hydrolyzed in vivo.
  • the promoieties are structurally and functionally defined herein.
  • R is —COR 90 , CO 2 R 91 , or CONR 92 R 93 wherein
  • R 90 and R 91 independently are C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 4-9 membered heterocycle, or a 5-10 membered heteroaryl, each containing at least 1 basic nitrogen moiety;
  • R 92 and R 93 independently are C 1 -C 6 alkyl; C 3 -C 8 cycloalkyl, 4-9 membered heterocycle, or a 5-10 membered heteroaryl, each containing at least 1 basic nitrogen moiety; or R 92 and R 93 together with the nitrogen atom they are bonded to for a 4-9 member heterocycle substituted with at least 1 amino, C 1 -C 6 alkyl amino, or di C 1 -C 6 alkylamino group.
  • R is —C(O)R 31 , C(O)OR 31 , or CON(R 13 ) 2 ,
  • each R 31 is independently a C 1 -C 6 alkyl; C 3 -C 8 cycloalkyl, 4-9 membered heterocycle, or a 5-10 membered heteroaryl, containing at least 1 basic nitrogen moiety; and
  • each R 13 independently is C 1 -C 6 alkyl; C 3 -C 8 cycloalkyl, 4-9 membered heterocycle, or a 5-10 membered heteroaryl, containing at least 1 basic nitrogen moiety; or both R 13 together with the nitrogen atom they are bonded to for a 4-9 member heterocycle substituted with at least 1 amino, C 1 -C 6 alkyl amino, or di C 1 -C 6 alkylamino group.
  • R is C(O)OR 31 , C(S)OR 31 , C(O)SR 31 or COR 31 , wherein R 31 is as defined herein.
  • R 31 is a group of the formula (CR 32 R 33 )NR 34 R 35 , wherein
  • each R 32 and R 33 is independently H, a C 1 -C 8 alkyl, C 3 -C 9 heterocyclyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, C 3 -C 9 heteroaryl or R 32 and R 33 together with the carbon atom they are bond to form a C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, C 3 -C 9 heterocyclyl or C 3 -C 9 heteroaryl ring system, or 2 adjacent R 32 moieties or 2 adjacent R 33 moieties together with the carbon atom they are bond to form a C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, C 3 -C 9 heterocyclyl or C 3 -C 9 heteroaryl ring system;
  • each R 34 and R 35 is a C 1 -C 8 alkyl, C 3 -C 9 heterocyclyl, C 3 -C 8 cycloalkyl, or R 34 and R 35 together with the nitrogen atom they are bond to form a C 3 -C 8 cycloalkyl or C 3 -C 9 heterocyclyl ring system;
  • each heterocyclic and heteroaryl ring system is optionally substituted with C 1 -C 3 alkyl, —OH, amino and carboxyl groups;
  • e is an integer of from 1 to 4.
  • R 34 and R 35 can be hydrogen.
  • the subscript e is preferably 2 and each R 32 and R 33 is preferably independently selected from the group, H, CH 3 , and a member in which R 32 and R 33 are joined together to form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or 1,1-dioxo-hexahydro-1 ⁇ 6 -thiopyran-4-yl or tetrahydropyran-4-yl group.
  • preferred embodiments are compounds wherein NR 34 R 35 is morpholino.
  • R is:
  • each R 32 and R 33 is independently H.
  • C 1 -C 8 alkyl, or optionally, if both present on the same substituent, may be joined together to form a C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, C 3 -C 9 heterocyclyl or C 3 -C 9 heteroaryl ring system.
  • each R 32 and R 33 is independently, H, CH 3 , or are joined together to form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1,1-dioxo-hexahydro-1 ⁇ 6 -thiopyran-4-yl or tetrahydropyran-4-yl group.
  • linkage of the prodrug moiety to the rest of the active molecule is stable enough so that the serum half life of the prodrug is from about 8 to about 24 hours.
  • the prodrug moiety comprises a tertiary amine having a pKa near the physiological pH of 7.5. Any amines having a pKa within 1 unit of 7.5 are suitable alternatives amines for this purpose.
  • the amine may be provided by the amine of a morpholino group. This pKa range of 6.5 to 8.5 allows for significant concentrations of the basic neutral amine to be present in the mildly alkaline small intestine.
  • the basic, neutral form of the amine prodrug is lipophilic and is absorbed through the wall of the small intestine into the blood. Following absorption into the bloodstream, the prodrug moiety is cleaved by esterases which are naturally present in the serum to release an active compound.
  • R examples of R include, without limitation:
  • R is as tabulated below:
  • R is,
  • R is:
  • X 1 is selected from the group consisting of O, S and NR 37 wherein R 37 is hydrogen or C 1 -C 6 alkyl;
  • Y 1 is —C(R 38 ) 2 or a sugar moiety, wherein each R 38 is independently hydrogen or C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 9 heterocyclyl, C 6 -C 10 aryl, or C 3 -C 9 heteroaryl;
  • X 2 is selected from the group consisting of halogen, C 1 -C 6 alkoxy, diacylglycerol, amino, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, C 1 -C 6 alkylthio, a PEG moiety, a bile acid moiety, a sugar moiety, an amino acid moiety, a di- or tri-peptide, a PEG carboxylic acid, and —U—V wherein
  • U is O or S
  • V is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 9 heterocyclyl, C 6 -C 10 aryl, C 3 -C 9 heteroaryl, C(W 2 )X 3 , PO(X 3 ) 2 , and SO 2 X 3 ;
  • W 2 is O or NR 39
  • R 39 is hydrogen or C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 9 heterocyclyl, C 6 -C 10 aryl, or C 3 -C 9 heteroaryl;
  • each X 3 is independently amino, hydroxyl, mercapto, C 1 -C 6 alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, C 1 -C 6 alkylthio, a bile acid based alkoxy group, a sugar moiety, a PEG moiety, and —O—CH 2 —CH(OR 40 )CH 2 X 4 R 40 ,
  • X 4 is selected from the group consisting of O, S, S ⁇ O, and SO 2 ;
  • each R 40 is independently C 10 -C 22 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 9 heterocyclyl, C 6 -C 10 aryl, or C 3 -C 9 heteroaryl, C 1 -C 8 alkylene, or C 1 -C 8 heteroalkylene.
  • Each heterocyclic and heteroaryl ring system is optionally substituted with C 1 -C 3 alkyl, —OH, amino and carboxyl groups.
  • the present invention utilizes the following Y 1 groups: CH 2 , CHMe, CH(isopropyl), CH(tertiarybutyl), C(Me) 2 , C(Et) 2 , C(isopropyl) 2 , and C(propyl) 2 .
  • the present invention utilizes the following X 2 groups:
  • R 41 is a side chain C 1 -C 6 alkyl, or C 3 -C 9 heterocyclyl group selected from the side chain groups present in essential amino acids; —O—P( ⁇ O)(OMe) 2 , —O—P( ⁇ OXO-isopropyl) 2 , and —O—P( ⁇ O)(O-isobutyl) 2 .
  • Each heterocyclic is optionally substituted with one or more, preferably, 1-3, C 1 -C 3 alkyl, —OH, amino and/or carboxyl groups.
  • R is:
  • X 3 is independently C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 9 heterocyclyl, C 6 -C 10 aryl, or C 3 -C 9 heteroaryl;
  • R 42 is independently hydrogen or C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 9 heterocyclyl, C 6 -C 10 aryl, or C 3 -C 9 heteroaryl.
  • Each heterocyclic is optionally substituted with one or more, preferably, 1-3, C 1 -C 3 alkyl, —OH, amino and/or carboxyl groups.
  • R is:
  • each X 3 is independently amino, hydroxyl, mercapto, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 9 heterocyclyl, C 6 -C 10 aryl, or C 3 -C 9 heteroaryl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, C 1 -C 6 alkylthio, a bile acid based alkoxy group, a sugar moiety, a PEG moiety, and —O—CH 2 —CH(OR 40 )CH 2 X 4 R 40 ,
  • X 4 is selected from the group consisting of O, S, S ⁇ O, and SO 2 ;
  • each R 40 is independently C 10 -C 22 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 9 heterocyclyl, C 6 -C 10 aryl, C 3 -C 9 heteroaryl, C 1 -C 8 alkylene, or C 1 -C 8 heteroalkylene; and
  • R 42 is independently hydrogen or C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 9 heterocyclyl, C 6 -C 10 aryl, or C 3 -C 9 heteroaryl.
  • R 42 is independently hydrogen or C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 9 heterocyclyl, C 6 -C 10 aryl, or C 3 -C 9 heteroaryl; and each X 3 independently is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 9 heterocyclyl, C 6 -C 10 aryl, or C 3 -C 9 heteroaryl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, or C 1 -C 6 alkylthio.
  • R is represented by the following structures:
  • R 43 is C 10 -C 22 alkyl or alkylene
  • R 44 is H or C 1 -C 6 alkyl
  • R 45 represents side chain alkyl groups present in naturally occurring alpha amino acids
  • R is:
  • R is —C(R 200 R 201 )O(R 202 R 203 )P(O)OR NR 205 R 206 , wherein each R 200 , R 201 , R 202 , R 203 , R 204 R 205 and R 206 is independently H, a C 1 -C 8 alkyl, C 3 -C 9 heterocyclyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, C 3 -C 9 heteroaryl, wherein each alkyl, heterocyclyl, cycloalkyl, aryl, and heteroaryl is optionally substituted.
  • R is —CH(R 201 )OCH 2 P(O)OR 204 NHR 206 , wherein R 201 is C 1 -C 8 alkyl, R 204 is phenyl, optionally substituted.
  • R 206 is —CHR 207 C(O)OR 208 wherein R 207 is selected from the group consisting of the naturally occurring amino acid side chains and —CO 2 H esters thereof and R 208 is C 1 -C 8 alkyl.
  • R 206 is C 1 -C 6 alkyl, optionally substituted with 1-3, CO 2 H, SH, NH 2 , C 6 -C 10 aryl, and C 2 -C 10 heteroaryl.
  • R is:
  • R is:
  • Y 1 is —C(R 38 ) 2 , wherein each R 38 is independently hydrogen or C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 9 heterocyclyl, C 6 -C 10 aryl, or C 3 -C 9 heteroaryl.
  • PEG polyethylene glycol
  • R is
  • R 50 is —OH or hydrogen
  • R 51 is —OH, or hydrogen
  • W is —CH(CH 3 )W 1 ;
  • W 1 is a substituted C 1 -C 8 alkyl group containing a moiety which is optionally negatively charged at physiological pH
  • said moiety is selected from the group consisting of CO 2 H, SO 3 H, SO 2 H, —P(O)(OR 52 )(OH), —OP(O)(OR 52 )(OH), and OSO 3 H,
  • R 52 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 9 heterocyclyl, C 6 -C 10 aryl, or C 3 -C 9 heteroaryl.
  • Each heterocyclic and heteroaryl ring system is optionally substituted with one or more, preferably 1-3, C 1 -C 3 alkyl, —OH, amino and/or carboxyl groups.
  • R is:
  • R 53 is H or C 1 -C 6 alkyl.
  • R is SO 3 H.
  • R comprises a cleavable linker, wherein the term “cleavable linker” refers to a linker which has a short half life in vivo.
  • the breakdown of the linker Z in a compound releases or generates the active compound.
  • the cleavable linker has a half life of less than ten hours. In one embodiment, the cleavable linker has a half life of less than an hour. In one embodiment, the half life of the cleavable linker is between one and fifteen minutes.
  • the cleavable linker has at least one connection with the structure: C*—C( ⁇ X*)X*—C* wherein C* is a substituted or unsubstituted methylene group, and X* is S or O.
  • the cleavable linker has at least one C*—C( ⁇ O)O—C* connection.
  • the cleavable linker has at least one C*—C( ⁇ O)S—C* connection.
  • the cleavable linker has at least one —C( ⁇ O)N*—C*—SO 2 —N*-connection, wherein N* is —NH— or C 1 -C 6 alkylamino.
  • the cleavable linker is hydrolyzed by an esterase enzyme.
  • the linker is a self-immolating linker, such as that disclosed in U.S. patent publication 2002/0147138, to Firestone; PCT Appl. No. US05/08161 and PCT Pub. No. 2004/087075.
  • the linker is a substrate for enzymes. See generally Rooseboom et al., 2004. Pharmacol. Rev. 56:53-102.
  • composition comprising any of the compounds described herein, and at least a pharmaceutically acceptable excipient.
  • this invention provides a composition comprising any of the compounds described herein, and a pharmaceutically acceptable excipient.
  • compositions suitable for oral delivery can be formulated for different routes of administration.
  • routes that may be used include transdermal, intravenous, intraarterial, pulmonary, rectal, nasal, vaginal, lingual, intramuscular, intraperitoneal, intracutaneous, intracranial, and subcutaneous routes.
  • Suitable dosage forms for administering any of the compounds described herein include tablets, capsules, pills, powders, aerosols, suppositories, parenterals, and oral liquids, including suspensions, solutions and emulsions. Sustained release dosage forms may also be used, for example, in a transdermal patch form. All dosage forms may be prepared using methods that are standard in the art (see e.g., Remington's Pharmaceutical Sciences, 16th ed., A. Oslo editor, Easton Pa. 1980).
  • compositions in accordance with the invention are prepared by conventional means using methods known in the art.
  • compositions disclosed herein may be used in conjunction with any of the vehicles and excipients commonly employed in pharmaceutical preparations, e.g., talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous solvents, oils, paraffin derivatives, glycols, etc. Coloring and flavoring agents may also be added to preparations, particularly to those for oral administration. Solutions can be prepared using water or physiologically compatible organic solvents such as ethanol, 1,2-propylene glycol, polyglycols, dimethylsulfoxide, fatty alcohols, triglycerides, partial esters of glycerin and the like.
  • Solid pharmaceutical excipients include starch, cellulose, hydroxypropyl cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • the compositions provided herein comprises one or more of ⁇ -tocopherol, gum arabic, and/or hydroxypropyl cellulose.
  • this invention provides sustained release formulations such as drug depots or patches comprising an effective amount of a compound provided herein.
  • the patch further comprises gum Arabic or hydroxypropyl cellulose separately or in combination, in the presence of alpha-tocopherol
  • the hydroxypropyl cellulose has an average MW of from 10.000 to 100.000.
  • the hydroxypropyl cellulose has an average MW of from 5,000 to 50,000.
  • co-administration can be in any manner in which the pharmacological effects of both are manifest in the patient at the same time.
  • co-administration does not require that a single pharmaceutical composition, the same dosage form, or even the same route of administration be used for administration of both the compound of this invention and the other agent or that the two agents be administered at precisely the same time.
  • co-administration will be accomplished most conveniently by the same dosage form and the same route of administration, at substantially the same time. Obviously, such administration most advantageously proceeds by delivering both active ingredients simultaneously in a novel pharmaceutical composition in accordance with the present invention.
  • a method for increasing tissue and/or cellular oxygenation comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or compositions described herein.
  • a method for increasing oxygen affinity of hemoglobin S in a subject comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or compositions described herein.
  • a method for treating a condition associated with oxygen deficiency comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or compositions described herein.
  • a method for treating oxygen deficiency associated with sickle cell anemia comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or compositions described herein.
  • a method for treating sickle cell disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any of the compounds or compositions described herein.
  • a method for treating cancer, a pulmonary disorder, stroke, high altitude sickness, an ulcer, a pressure sore, Alzheimer's disease, acute respiratory disease syndrome, and a wound comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any of the compounds or compositions described herein.
  • the reactions are preferably carried out in a suitable inert solvent that will be apparent to the skilled artisan upon reading this disclosure, for a sufficient period of time to ensure substantial completion of the reaction as observed by thin layer chromatography, 1 H-NMR, etc. If needed to speed up the reaction, the reaction mixture can be heated, as is well known to the skilled artisan.
  • the final and the intermediate compounds are purified, if necessary, by various art known methods such as crystallization, precipitation, column chromatography, and the likes, as will be apparent to the skilled artisan upon reading this disclosure.
  • a 5 and B 5 are independently NR 14 , O, S, S(O)x, NBoC, CH 2 , CHR 14 , C(R 14 ) 2 provided that when both A 5 and B 5 are present in a ring, both are not CH 2 , CHR 14 , C(R 14 ) 2 , and that when only 1 A 5 or B 5 is present in a ring the A 5 or B 5 is not CH 2 , CHR 14 , C(R 14 ) 2 ;
  • R 14 is C 1 -C 6 alkyl, COR 15 or COOR 15 ; wherein R 15 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 6 -C 10 aryl, optionally substituted 5-10 membered heteroaryl containing up to 5 ring heteroatoms, or optionally substituted 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S;
  • X, and X 5 each represents a leaving group and are independently selected from Cl, Br, and I.
  • X 6 represents CR, N, O, S(O)x; wherein x is 0, 1, or 2;
  • R 71 is C 1 -C 6 alkyl
  • Y 5 represents a leaving group selected from Cl, F, Br, I, OSO 2 R 17 and OSO 2 Ar;
  • Ar is phenyl optionally substituted with 1-3 halo and/or C 1 -C 4 alkyl;
  • n 0, 1, or 2;
  • a solution of aqueous 1N Na 2 CO 3 is then added to produce a solution of pH-8, the mixture was extracted with DCM (3 ⁇ 10-50 mL), dried over sodium sulfate, and concentrated to the crude substituted methylene chloride (2a), which is then purified by column chromatography on silica gel (0-100% ethyl acetate-hexanes).
  • Step 1 Condensation of heterocyclic ketone analog 5 with chlorformate or dialkyl carbonate gives (hetero)cyclic beta-ketone ester 6 (Step 1).
  • the ketone ester 6 is converted to the triflate intermediate 7 by treating with a triflating agent (e.g, triflic anhydride) in the presence of an organic base such as Hunig's base (Step 2).
  • a triflating agent e.g, triflic anhydride
  • Suzuki coupling of the triflate 7 with a boronic acid or ester affords heterocyclohexene carboxylate 8 (Step 3).
  • Subsequent reduction of the ester group by LAH or DIBAL gives the corresponding alcohol 9-OH (Step 4).
  • the double bond of heterocyclohexene carboxylate 8 is reduced to give the cis-heterocyclohexane 11-cis carboxylate under palladium catalyzed hydrogenation conditions (Step 6).
  • Reduction of the ester group of 11-cis by LAH or DIBAL yields cis-alcohol 12-OH-cis (Step 8).
  • Conversion of the alcohol 12-OH-cis to its chloride, bromide or sulfonate (such as mesylate, tosylate) 13-X-cis can be achieved by reacting with thionyl chloride, or Ph 3 PBr 2 , or sulfonyl chloride (such as mesyl chloride or tosyl chloride) (Step 9).
  • the cis-cyclohexane carboxylate 11-cis can also be isomerized to the thermodynamically more stable trans-isomer 11-trans by the treatment with an alcoholic alkoxide (e.g., ethoxide) solution.
  • transformation of 11-trans ester to 12-trans alcohol and 13-X-trans halide is accomplished by applying conditions of Step 8 and Step 9 (Scheme 2) similar to these for the corresponding cis-isomers.
  • N-linked heterocyclic analogs (compound 5, Scheme 4) can also be synthesized from amination procedures developed by Buchwald and Hartwig.
  • Syntheses of the ester prodrugs start with the free carboxylic acid bearing the tertiary amine.
  • the free acid is activated for ester formation in an aprotic solvent and then reacted with a free alcohol group in the presence of an inert base, such as triethyl amine, to provide the ester prodrug.
  • Activating conditions for the carboxylic acid include forming the acid chloride using oxalyl chloride or thionyl chloride in an aprotic solvent, optionally with a catalytic amount of dimethyl formamide, followed by evaporation.
  • aprotic solvents include, but are not limited to methylene chloride, tetrahydrofuran, and the like.
  • activations can be performed in situ by using reagents such as BOP (benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorolphosphate, and the like (see Nagy et al., 1993. Proc. Natl. Acad. Sci. USA 90:6373-6376) followed by reaction with the free alcohol.
  • BOP benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorolphosphate
  • Isolation of the ester products can be affected by extraction with an organic solvent, such as ethyl acetate or methylene chloride, against a mildly acidic aqueous solution; followed by base treatment of the acidic aqueous phase so as to render it basic; followed by extraction with an organic solvent, for example ethyl acetate or methylene chroride; evaporation of the organic solvent layer; and recrystalization from a solvent, such as ethanol.
  • the solvent can be acidified with an acid, such as HCl or acetic acid to provide a pharmaceutically acceptable salt thereof.
  • the crude reaction can be passed over an ion exchange column bearing sulfonic acid groups in the protonated form, washed with deionized water, and eluted with aqueous ammonia; followed by evaporation.
  • Suitable free acids bearing the tertiary amine are commercially available, such as 2-(N-morpholino)-propionic acid, N,N-dimethyl-beta-alanine, and the like. Non-commercial acids can be synthesized in straightforward manner via standard literature procedures.
  • Carbonate and carbamate prodrugs can be prepared in an analogous way.
  • amino alcohols and diamines can be activated using activating agents such as phosgene or carbonyl diimidazole, to provide an activated carbonates, which in turn can react with the alcohol and/or the phenolic hydroxy group on the compounds utilized herein to provide carbonate and carbamate prodrugs.
  • Scheme 5 provides a method of synthesizing an acyloxymethyl version of a prodrug by adapting a method from the reference Sobolev et al., 2002, J. Org. Chem. 67:401-410.
  • R 51 is C 1 -C 6 alkyl.
  • Scheme 6 provides a method for synthesizing a phosphonooxymethyl version of a prodrug by adapting a method from Mantyla et al., 2004, J. Med. Chem. 47:188-195.
  • Scheme 7 provides a method of synthesizing an alkyloxymethyl version of a prodrug
  • R 52 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 9 heterocyclyl, C 6 -C 10 aryl, or C 3 -C 9 heteroaryl.
  • the carboxylate 14a (1-10 mmol) is first dissolved in DMF (2-20 mL); to this was then added a base such as NaH or Cs 2 CO 3 (1-1.2 eq), followed by the addition of alkyl halide (eg, BnBr) (0.9-1.5 eq).
  • alkyl halide eg, BnBr
  • a solution of aqueous 1N Na 2 CO 3 is then added to produce a solution of pH ⁇ 8, the mixture was extracted with DCM (3 ⁇ 10-50 mL), dried over sodium sulfate, and concentrated to the crude substituted methylene chloride (3a), which is then purified by column chromatography on silica gel (0-100% ethyl acetate-hexanes).
  • Methylmagnesium bromide (3M/ether, 41.0 mL, 123.4 mmol) was added to a stirred solution of 3-((tert-butyldimethylsilyloxy)methyl)picolinonitrile (20.4 g, 82.25 mmol) in THF (100.0 mL) at ⁇ 78° C.
  • the reaction mixture was warm to RT, quenched with aqueous citric acid solution, and extracted with EtOAc (50 mL) twice.
  • the mixture was then stirred at ⁇ 40° C. for 1 h, quenched with a mixture of HCl (12 N, 12 mL) and THF (28 mL), warmed to RT, and added water (20 mL). The pH of the mixture was adjusted to pH 8-9 with solid K 2 CO 3 . The aqueous layer was extracted with EtOAc (30 mL) twice.
  • Step 2 To a mixture of 2-methoxy-5-(methoxymethoxy)pyridine (30 g, 0.178 mol) and diisopropylamine (507 uL, 3.6 mmol) in THF (500 mL) was added methyl lithium (1.6 M/THF, 200 mL, 0.32 mol) at ⁇ 40° C. Upon the completion of addition, the mixture was warmed to 0° C. and continued to stir at 0° C. for 3 h. The reaction mixture was then cooled back down to ⁇ 40° C. followed by addition of DMF (24.7 mL, 0.32 mol) slowly. The mixture was then stirred at ⁇ 40° C.
  • GTB527 was prepared using general method B from 5-hydroxy-2-methoxyisonicotinaldehyde and INT-2.
  • GTB779 was prepared according to general method B from 5-hydroxy-2-(2-morpholinoethoxy)isonicotinaldehyde and INT-4.
  • GTB832 was prepared according to general method B from 5-hydroxy-2-(2-methoxyethoxy)isonicotinaldehyde (INT-5) and INT-2.
  • GTB835 was prepared according to general method B from 3-hydroxy-6-methylpicolinaldehyde and INT-2.
  • GTB836 was prepared according to general method B from 3-hydroxy-6-methylpicolinaldehyde and INT-3.
  • GTB839 was prepared according to general method B from 3-hydroxypicolinaldehyde and INT-2.
  • GTB839 was prepared according to general method B from 3-hydroxypicolinaldehyde and INT-3.
  • GTB841 was prepared according to general method B from 3-chloro-5-hydroxyisonicotinaldehyde and INT-4.
  • GTB844 was prepared according to general method B from 3-chloro-5-hydroxyisonicotinaldehyde and INT-2.
  • the crude product (200 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.1% HCOOH and MeCN (10.0% MeCN up to 40.0% in 10 min, up to 95.0% in 2 min, down to 10.0% in 2 min); Detector, Waters2545 UvDector 254&220 nm. This resulted in 65 mg (9%) of 2-methoxy-5-[[2-(2-methoxyphenyl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde bis(trifluoroacetic acid) as a yellow solid.
  • Prep-HPLC-010 Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm
  • mobile phase water with 0.1% HCOOH and MeCN (10.0% MeCN up to 40.0% in 10 min, up to 95.0% in 2 min, down to 10.
  • Step 1 Into a 50-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of (3-methoxyphenyl)boronic acid (1.6 g, 10.53 mmol, 1.20 equiv), (2-chloropyridin-3-yl)methanol (1 g, 6.97 mmol, 1.00 equiv), sodium bicarbonate (1.7 g, 20.24 mmol, 3.00 equiv), Pd(dppf)Cl 2 (0.57 g, 0.10 equiv) in a solvent mixture of dioxane (10 mL) and water (10 mL).
  • the crude product (200 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.1% TFA and MeCN (20% MeCN up to 40% in 10 min, up to 95% in 2 min, down to 20% in 1 min); Detector, Waters2545 UvDector 254&220 nm. This resulted in 100.8 mg (17%) of 2-methoxy-5-[[2-(3-methoxyphenyl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde bis(trifluoroacetic acid) as a yellow solid.
  • Prep-HPLC-010 Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm
  • mobile phase water with 0.1% TFA and MeCN (20% MeCN up to 40% in 10 min, up to 95% in 2 min, down to 20% in 1 min
  • Detector Water
  • Step 1 Into a 50-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of (4-methoxyphenyl)boronic acid (1.6 g, 10.53 mmol, 1.20 equiv), (2-chloropyridin-3-yl)methanol (1 g, 6.97 mmol, 1.00 equiv), sodium bicarbonate (1.7 g, 20.24 mmol, 3.00 equiv), Pd(dppf)Cl 2 (0.57 g, 0.10 equiv) in a solvent mixture of dioxane (10 mL) and water (10 mL).
  • the crude product (300 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.1% TFA and MeCN (20.0% MeCN up to 50.0% in 10 min, up to 95.0% in 2 min, down to 20.0% in 1 min); Detector, Waters2545 UvDector 254&220 nm. This resulted in 265.1 mg (46%) of 2-methoxy-5-[[2-(4-methoxyphenyl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde; bis(trifluoroacetic acid) as a brown oil.
  • Prep-HPLC-010 Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm
  • mobile phase water with 0.1% TFA and MeCN (20.0% MeCN up to 50.0% in 10 min, up to 95.0% in 2 min,
  • the product as a yellow film was contained after removing solvents, the residue was re-dissolved in 0.3 mL CH 3 CN and to this was added 0.5 mL of water. This suspension was freezed and put on a lyophilizer over the weekend. The product was obtained as a light brown film (18.6 mg, 34% yield).
  • the crude product (300 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and MeCN (20.0% MeCN up to 60.0% in 10 min, up to 95.0% in 2 min, down to 20.0% in 1 min); Detector, Waters2545 UvDector 254&220 nm. This resulted in 71 mg (9%) of 5-[[2-(3-chlorophenyl)pyridin-3-yl]methoxy]-2-methoxypyridine-4-carbaldehyde; bis(trifluoroacetic acid) as a yellow solid.
  • Prep-HPLC-010 Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm
  • mobile phase water with 0.05% TFA and MeCN (20.0% MeCN up to 60.0% in 10 min, up to 95.0% in 2 min
  • Step 1 Into a 100-mL round-bottom flask, was placed a solution of (4-chlorophenyl)boronic acid (1.6 g, 10.23 mmol, 1.20 equiv), (2-chloropyridin-3-yl)methanol (1 g, 6.97 mmol, 1.00 equiv), Pd(dppf)Cl 2 (570 mg, 0.78 mmol, 0.10 equiv), and sodium bicarbonate (1.7 g, 20.24 mmol, 3.00 equiv) in a solvent mixture of dioxane (10 mL) and water (10 mL).
  • the crude product (300 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm: mobile phase, water with 0.05% TFA and MeCN (20.0% MeCN up to 60.0% in 10 min, up to 95.0% in 2 min, down to 20.0% in 1 min); Detector, Waters2545 UvDector 254&220 nm. This resulted in 148.2 mg (20%) of 5-[[2-(4-chlorophenyl)pyridin-3-yl]methoxy]-2-methoxypyridine-4-carbaldehyde; bis(trifluoroacetic acid) as a yellow solid.
  • Prep-HPLC-010 Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm: mobile phase, water with 0.05% TFA and MeCN (20.0% MeCN up to 60.0% in 10 min, up to 95.0% in
  • the compound was prepared from (2-chloropyridin-3-yl)methanol and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole according to scheme 9, reaction steps 1, 2 and 4.
  • step 4 2-hydroxy-6-(methoxymethoxy)benzaldehyde was used; the MOM ether protecting group fell off after the reaction to give the final product.
  • GBT907 and GBT908 Preparation of (S)-2-hydroxy-6-((1-(2-methoxyphenyl)pyrrolidin-2-yl)methoxy)benzaldehyde (GBT907) and 2-hydroxy-6-((1-(2-methoxyphenyl)piperidin-3-yl)oxy)benzaldehyde (GBT908)
  • GBT912 2-(((3S,4R)-1-acetyl-4-(2,5-difluorophenyl)pyrrolidin-3-yl)methoxy)-6-hydroxybenzaldehyde
  • the compound was prepared from -(2,5-difluorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl)ethan-1-one and 2,6-dihydroxybenzaldehyde (INT-7) using general method A (Mitsunobu conditions).
  • GBT913 and GBT914 Preparation of (S)-2-hydroxy-6-((1-(3-methoxyphenyl)pyrrolidin-2-yl)methoxy)benzaldehyde (GBT913) and 2-hydroxy-6-((1-(3-methoxyphenyl)piperidin-3-yl)oxy)benzaldehyde (GBT914)
  • GBT916 2-hydroxy-6-((2-(2-methoxyphenyl)pyridin-3-yl)methoxy)benzaldehyde
  • the compound was prepared from (2-chloropyridin-3-yl)methanol and (2-methoxyphenyl)boronic acid according to scheme 9, reaction steps 1, 2 and 4.
  • step 4 alkylation with 2,6-dihydroxybenzaldehyde, the product of TFA salt was obtained after HPLC purification.
  • GBT917 2-hydroxy-6-((2′-methoxy-[2,3′-bipyridin]-3-yl)methoxy)benzaldehyde
  • the compound was prepared from (2-chloropyridin-3-yl)methanol and (2-methoxypyridin-3-yl)boronic acid according to scheme 9, reaction steps 1, 2 and 4.
  • step 4 alkylation with 2,6-dihydroxybenzaldehyde, the product TFA salt was obtained after HPLC purification.
  • GBT930 2-((2-(1-cyclobutyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-6-hydroxybenzaldehyde
  • the compound was prepared by Mitsunobu reaction (scheme 9, step 3) of (2-(1-cyclobutyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol (A) with 2,6-dihydroxybenzaldehyde (INT3).
  • the product was obtained as pale yellow solid.
  • Step 1 Into a 500-mL round-bottom flask, was placed a solution of 1H-pyrazole (10 g, 146.89 mmol, 1.00 equiv), Cs 2 CO 3 (95.9 g, 294.33 mmol, 2.00 equiv), and bromocyclobutane (29.7 g, 220.00 mmol, 1.50 equiv) in CH 3 CN (150 mL). The resulting solution was stirred overnight at 80° C., and then it was concentrated under vacuum.
  • 1H-pyrazole 10 g, 146.89 mmol, 1.00 equiv
  • Cs 2 CO 3 95.9 g, 294.33 mmol, 2.00 equiv
  • bromocyclobutane 29.7 g, 220.00 mmol, 1.50 equiv
  • Step 2 Into a 250-mL round-bottom flask, was placed a solution of 1-cyclobutyl-1H-pyrazole (6.5 g, 53.21 mmol, 1.00 equiv) in tetrahydrofuran (100 ml). This was followed by the addition of BuLi (2.5 M, 22.7 mL, 1.10 equiv) dropwise with stirring at ⁇ 30° C. The mixture was stirred for 30 min at the same temperature. To this was added 4,4,5,5-tetramethyl-2-(propan-2-yloxy)-1,3,2-dioxaborolane (14.9 g, 80.08 mmol, 1.50 equiv) dropwise with stirring at ⁇ 78° C.
  • Step 3 Into a 100-mL round-bottom flask, was placed a solution of 1-cyclobutyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (791 mg, 3.19 mmol, 2.00 equiv), (2-bromopyridin-3-yl)methanol (500 mg, 2.66 mmol, 1.00 equiv), Pd(dppf)Cl 2 (217 mg, 0.30 mmol, 0.10 equiv), and sodium carbonate (670 mg, 6.32 mmol, 3.0) equiv) in a solvent mixture of dioxane (10 mL) and water (10 mL).
  • GBT934 2-((2′-ethoxy-[2,3′-bipyridin]-3-yl)methoxy)-6-hydroxybenzaldehyde
  • the compound was prepared from (2-chloropyridin-3-yl)methanol and ((2-ethoxypyridin-3-yl)boronic acid according to scheme 9, reaction steps 1, 2 and 4.
  • step 4 alkylation with 2,6-dihydroxybenzaldehyde (INT3), the product TFA salt as white solid was obtained after HPLC purification.
  • GBT948 3-chloro-2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
  • the compound was prepared using general reaction step 4 of scheme 9, by O-alkylation of 3-chloro-6-hydroxy-2-(methoxymethoxy)benzaldehyde (B) with 3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine (A) and subsequent deprotection of the MOM ether by treating with aqueous 6N HCl in THF.
  • the MOM-protected phenol aldehyde intermediate B was prepared according to the following synthetic scheme:
  • Step 1 Into a 2000-mL round-bottom flask, was placed a solution of 4-chlorobenzene-1,3-diol (50.0 g, 345.89 mmol, 1.00 equiv) and potassium carbonate (95 g, 687.36 mmol, 2.00 equiv) in acetone (1000 mL). This was followed by the addition of MOMBr (40 g, 320.10 mmol, 0.90 equiv) dropwise with stirring. The resulting solution was stirred for 60 h at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum.
  • Step 2 Into a 1000-mL round-bottom flask, was placed a solution of 4-chloro-3-(methoxymethoxy)phenol (49.0 g, 259.80 mmol, 1.00 equiv) and potassium carbonate (57.4 g, 415.31 mmol, 1.60 equiv) in acetone (500 mL). This was followed by the addition of BnBr (55 g, 321.58 mmol, 1.20 equiv) dropwise with stirring in 40 min. The resulting solution was stirred overnight at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum.
  • Step 3 Into a 500-mL three neck round-bottom flask, was placed a solution of bis(propan-2-yl)amine (29.7 g, 293.51 mmol, 5.00 equiv) in tetrahydrofuran (70 mL). This was followed by the addition of BuLi (100 mL, 3.00 equiv) dropwise with stirring at ⁇ 78° C. The mixture was stirred for 10 min at ⁇ 78° C., then stirred for 10 min at 0° C.
  • the resulting solution was diluted with 50 mL of water.
  • the resulting solution was extracted with 3 ⁇ 100 mL, of ethyl acetate and the organic layers combined and dried over sodium sulfate and concentrated under vacuum.
  • the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) as eluent. This resulted in 8.8 g (34%) of 6-(benzyloxy)-3-chloro-2-(methoxymethoxy)benzaldehyde as a yellow solid.
  • Step 4 Into a 500-mL round-bottom flask, was placed a solution of 6-(benzyloxy)-3-chloro-2-(methoxymethoxy)benzaldehyde (8.8 g, 28.69 mmol, 1.00 equiv) in ethyl acetate (100 mL). Rh/C (1.0 g) was added to the reaction. The resulting solution was stirred for 20 h at room temperature under 1 atm of hydrogen gas. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2) as eluent. This resulted in 5.2 g (84%) of 3-chloro-6-hydroxy-2-(methoxymethoxy)benzaldehyde as a light yellow solid.
  • the compound was prepared by Mitsunobu reaction (scheme 9, step 3) of 2-hydroxy-4-(methoxymethoxy)benzaldehyde (A) with (2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol (B) and subsequent deprotection of the MOM ether by treating with aqueous 6N HCl in THE according the scheme below.
  • the compound was prepared from (2-chloropyridin-3-yl)methanol and 2,6-dimethoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine according to scheme 9, reaction steps 1, 2 and 4.
  • step 4 alkylation with 2,6-dihydroxybenzaldehyde, the product of TFA salt as white solid was obtained after HPLC purification.
  • GBT985 3-(difluoromethyl)-1-methyl-5-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-1H-pyrazole-4-carbaldehyde
  • GBT986 1-methyl-5-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde
  • GBT1065 4-fluoro-7-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2,3-dihydro-1H-inden-1-one bis(2,2,2-trifluoroacetate)
  • the compound was prepared by Mitsunobu reaction of 4-fluoro-7-hydroxy-2,3-dihydro-1H-inden-1-one with [2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]methanol according to scheme 9, reaction step 3.
  • the product TFA salt as white solid was obtained after HPLC purification.
  • GBT1133 2-(((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)oxy)methyl)benzaldehyde
  • the compound was prepared from ethyl 2-(bromomethyl)benzonitrile in 2 steps according to reaction scheme below.
  • the resulting solution was diluted with 20 mL of H 2 O, and then it was extracted with 3 ⁇ 20 mL of ethyl acetate. The combined organic layers were washed with 1 ⁇ 30 mL of brine and concentrated under vacuum.
  • the crude product (200 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and MeCN (38.0% MeCN up to 55.0% in 8 min); Detector, nm.
  • GBT1197 2-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
  • the compound was prepared by O-alkylation of 2-hydroxybenzaldehyde with 3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine (INT-4).
  • the product of TFA salt as white solid was obtained after HPLC purification.
  • the compound was prepared by Mitsunobu reaction of (6-bromo-2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol (intermediate A) and 2,6-dihydroxybenzaldehyde (INT-3) according to scheme 9, reaction step 3.
  • the product as white solid was obtained after flash column purification.
  • Step 1 Into a 500-mL round-bottom flask, was placed a solution of 2,6-dichloropyridine-3-carboxylic acid (25 g, 130.21 mmol, 1.00 equiv) in methanol (350 mL). This was followed by the addition of t-BuOK (43.8 g, 390.34 mmol, 3.00 equiv), in portions at 0° C. The resulting solution was heated to reflux for 3 days. The resulting mixture was concentrated under vacuum, and then it was diluted with 400 mL of water. The pH value of the solution was adjusted to 1 with hydrogen chloride aq. The solids were collected by filtration. The solid was dried in an oven under reduced pressure. This provided 20.5 g (84%) of 2-chloro-6-methoxypyridine-3-carboxylic acid as a white solid.
  • Step 2 Into a 100-mL round-bottom flask, was placed a solution of 2-chloro-6-methoxypyridine-3-carboxylic acid (11.3 g, 60.24 mmol, 1.00 equiv) in methanol (50 mL). This was followed by the addition of SOCl 2 (26 mL, 5.00 equiv) dropwise with stirring at 0 OC. The resulting solution was stirred for 1 h at room temperature and for an additional 2 h at reflux. The resulting solution was diluted with 100 mL of water. The pH value of the solution was adjusted to 10 with 2M sodium carbonate aq. The resulting solution was extracted with 3 ⁇ 80 mL of ethyl acetate and the organic layers combined.
  • Step 3 Into a 100-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed methyl 2-chloro-6-methoxypyridine-3-carboxylate (3.29 g, 16.32 mmol, 1.00 equiv), 1-(propan-2-yl)-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.63 g, 19.61 mmol, 1.20 equiv), toluene (45 mL), ethanol (15 mL), sodium carbonate (2M in H 2 O) (15 mL).
  • Step 4 Into a 250-mL round-bottom flask, was placed methyl 6-methoxy-2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridine-3-carboxylate (3.6 g, 13.08 mmol, 1.00 equiv), C 6 H 6 (60 mL), H 3 PO 4 (85%) (150 mg, 1.53 mmol, 0.10 equiv), PyHBr (208 mg, 1.30 mmol, 0.10 equiv), POBr 3 (11.5 g, 40.11 mmol, 3.00 equiv). The resulting solution was heated to reflux for 40 h. The reaction mixture was cooled to 0° C. with an ice bath.
  • the pH value of the solution was adjusted to 10 with potassium carbonate sat.
  • the resulting solution was extracted with 3 ⁇ 80 mL of ethyl acetate and the organic layers combined.
  • the resulting mixture was washed with 2 ⁇ 50 mL, of water and 1 ⁇ 50 mL of brine.
  • the mixture was dried over anhydrous sodium sulfate and concentrated under vacuum.
  • the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10-1:8) as eluent. This provided 2.62 g (62%) of methyl 6-bromo-2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridine-3-carboxylate as a yellow oil.
  • Step 5 Into a 50-mL round-bottom flask, was placed methyl 6-bromo-2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridine-3-carboxylate (2.62 g, 8.08 mmol, 1.00 equiv), tetrahydrofuran (30 mL). This was followed by the addition of LiBH 4 (350 mg, 16.07 mmol, 2.00 equiv) at 0° C. The resulting solution was stirred for 30 min at 0° C. and for an additional 1 h at room temperature. The reaction mixture was cooled to 0° C. with an ice bath. The reaction was then quenched by the addition of 20 mL of water.
  • LiBH 4 350 mg, 16.07 mmol, 2.00 equiv
  • the resulting solution was extracted with 3 ⁇ 60 mL of ethyl acetate and the organic layers combined.
  • the resulting mixture was washed with 2 ⁇ 50 mL of water and 1 ⁇ 50 mL of brine.
  • the mixture was dried over anhydrous sodium sulfate and concentrated under vacuum.
  • the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:8-1:5) as eluent to furnish 1.97 g quenched by the addition of 100 mL of sodium hydroxide (aq).
  • the pH value of the solution was adjusted to 12 with sodium hydroxide (aq).
  • the resulting solution was extracted with 3 ⁇ 60 mL of ethyl acetate.
  • Step 3 Into a 50-mL round-bottom flask, was placed a solution of 4-(dimethylamino)-2,6-dimethoxybenzaldehyde (3) (630 mg, 3.01 mmol, 1.00 equiv) in dichloromethane (25 mL). AlCl 3 (6 g, 45.11 mmol, 12.50 equiv) was added to the reaction. The resulting solution was heated to reflux for 24 h. The pH value of the solution was adjusted to 8-9 with sodium bicarbonate (aq). The resulting solution was extracted with 3 ⁇ 80 mL of ethyl acetate.
  • Step 4 Into a 25-mL round-bottom flask, was placed a solution of [2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]methanol (5) (132 mg, 0.61 mmol, 1.00 equiv), 4-(dimethylamino)-2,6-dihydroxybenzaldehyde (4) (110 mg, 0.61 mmol, 1.00 equiv), PPh 3 (207.3 mg, 0.79 mmol, 1.30 equiv) in tetrahydrofuran (10 mL). DIAD (160 mg, 0.79 mmol, 1.30 equiv) was added to the reaction dropwise at 0° C.
  • DIAD 160 mg, 0.79 mmol, 1.30 equiv
  • the resulting solution was stirred for 10 min at 0° C. and for an additional 2 h at room temperature. The reaction was then quenched with 10 mL of water. The resulting solution was extracted with 3 ⁇ 40 ml, of ethyl acetate. The combined organic layers were washed with 3 ⁇ 20 mL of water and 1 ⁇ 20 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum.
  • the crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and MeCN (30.0% MeCN up to 60.0% in 10 min.
  • Step 1 Into a 250-mL round-bottom flask, was placed a solution of 3,5-dimethoxyaniline (1) (4.6 g, 30.03 mmol, 1.00 equiv) and potassium carbonate (14.6 g, 105.64 mmol, 4.00 equiv) in N,N-dimethylformamide (80 mL). This was followed by the addition of SO 2 (OMe) 2 (8.4 g, 66.67 mmol, 2.00 equiv) dropwise with stirring at 0° C. The mixture was stirred for 2 h at 0° C. The resulting solution was stirred overnight at room temperature, and then it was quenched by the addition of 100 mL of water.
  • 3,5-dimethoxyaniline (1) 4 g, 30.03 mmol, 1.00 equiv
  • potassium carbonate 14.6 g, 105.64 mmol, 4.00 equiv
  • N,N-dimethylformamide 80 mL
  • Step 2 Into a 50-mL round-bottom flask, was placed a solution of 3,5-dimethoxy-N,N-dimethylaniline (2) (2.4 g, 13.24 mmol, 1.00 equiv) in N,N-dimethylformamide (25 mL). This was followed by the addition of POCl 3 (2.57 g, 16.76 mmol, 1.30 equiv) dropwise with stirring at 0° C. The resulting solution was stirred for 15 min at 0° C., and then it was
  • Step 1 Into a 250-mL round-bottom flask, was placed a solution of methyl 3-hydroxybenzoate (3 g, 19.72 mmol, 1.00 equiv) in trifluoroacetic acid (100 mL). Urotropin (5.5 g, 39.29 mmol, 2.00 equiv) was added to the reaction. The resulting solution was heated to reflux for 2 hr. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) as eluent to furnish 0.5 g (14%) of methyl 2-formyl-3-hydroxybenzoate as a yellow solid.
  • Step 2 Into a 100-mL round-bottom flask, was placed a solution of methyl 2-formyl-3-hydroxybenzoate (400 mg, 2.22 mmol, 1.00 equiv) in CH3CN (30 mL). 3-(Chloromethyl)-2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridine (523 mg, 2.22 mmol, 1.00 equiv), potassium carbonate (927 mg, 6.71 mmol, 3.00 equiv), and KI (40 mg, 0.24 mmol, 0.10 equiv) were added to the reaction. The resulting solution was stirred for 2 h at 60° C., and then it was diluted with 200 ml of EA.
  • Step 3 Into a 100-mL round-bottom flask, was placed a solution of methyl 2-formyl-3-([2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]methoxy)benzoate (100 mg, 0.26 mmol, 1.00 equiv) in tetrahydrofuran (10 mL). This was followed by the addition of a solution of sodium hydroxide (22 mg, 0.55 mmol, 2.00 equiv) in water (3 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 3 h at room temperature. The pH value of the solution was adjusted to 6 with hydrogen chloride (3 mol/L).
  • Prep-HPLC Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and MeCN (30% MeCN up to 600/o in 10 min, up to 95% in 3 min, down to 30% in 2 min); Detector, Waters2545 UvDector 254&220 nm.
  • Step 1 To a suspension of (S)-5-(hydroxymethyl)pyrrolidin-2-one (230 mg, 2 mmol) and iodobenzene (0.49 g, 2.4 mmol) in Dioxane (4 mL) was added CuI (0.08 g, 0.4 mmol), N,N-dimethylethylenediamine (0.05 mL, 0.4 mmol), K 2 CO 3 (0.55 g, 4 mmol). After heating at 100° C.
  • Step 2 To a solution of (S)-5-(hydroxymethyl)-1-phenylpyrrolidin-2-one (100 mg, 0.52 mmol) and 2,6-dihydroxybenzaldehyde (0.09 g, 0.65 mmol) in THF (5 mL) at 0° C. was added PPh 3 (polymer supported, 650 mg, 0.78 mmol) and DIAD (0.16 mL, 0.78 mmol).
  • Step 1 To a suspension of (S)-5-(hydroxymethyl)pyrrolidin-2-one (230 mg, 2 mmol) and 1-iodo-2-methoxybenzene (0.56 g, 2.4 mmol) in Dioxane (4 mL) was added CuI (0.08 g, 0.4 mmol), N,N-dimethylethylenediamine (0.05 mL, 0.4 mmol), K 3 PO 4 (0.85 g, 4 mmol). After heating at 100° C.
  • Step 2 To a solution of (S)-5-(hydroxymethyl)-1-phenylpyrrolidin-2-one (115 mg, 0.54 mmol) and 2,6-dihydroxybenzaldehyde (0.10 g, 0.70 mmol) in THF (4 mL) at 0 CC was added PPh 3 (polymer supported, 675 mg, 0.81 mmol) and DIAD (0.16 mL, 0.81 mmol).
  • GBT1004 2-amino-4-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy) nicotinaldehyde
  • Step 1 Into a 250-mL round-bottom flask, was placed a solution of 4-chloropyridin-2-amine (10 g, 77.78 mmol, 1.00 equiv) in tetrahydrofuran (150 mL). This was followed by the addition of LiHMDS(1 M) (156 mL) dropwise with stirring at 0° C. The mixture was stirred for 20 min at 0° C. To this was added Boc 2 O (17.02 g, 77.98 mmol, 1.00 equiv). The resulting solution was stirred for 1 h at 0° C. The reaction was then quenched by the addition of 100 mL of NH 4 Cl.
  • Step 2 Into a 100-mL three neck round-bottom flask, was placed a solution of tert-butyl N-(4-chloropyridin-2-yl)carbamate (2 g, 8.75 mmol, 1.00 equiv) in tetrahydrofuran (50 mL). This was followed by the addition of BuLi (2.5M) (7.0 mL, 2.00 equiv) dropwise with stirring at ⁇ 78° C. in 20 min. The mixture was stirred for 0.5 h at ⁇ 78° C. To this was added N,N-dimethylformamide (2.0 mL, 3.00 equiv) dropwise with stirring at ⁇ 78° C. in 5 min.
  • BuLi 2.5M
  • N,N-dimethylformamide 2.0 mL, 3.00 equiv
  • Step 3 Into a 100-mL round-bottom flask, was placed a solution of [2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]methanol (500 mg, 2.30 mmol, 1.20 equiv) in N,N-dimethylformamide (50 mL). This was followed by the addition of sodium hydride (190 mg, 7.92 mmol, 2.50 equiv) at 0° C. The mixture was stirred for 20 min at 0° C. To this was added tert-butyl N-(4-chloro-3-formylpyridin-2-yl)carbamate (500 mg, 1.95 mmol, 1.00 equiv).
  • Step 4 Into a 100-mL round-bottom flask, was placed a solution of trifluoroacetic acid (10 mL) in dichloromethane (60 mL), tert-butyl N-[3-formyl-4-([2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]methoxy)pyridin-2-yl]carbamate (500 mg, 1.14 mmol, 1.00 equiv). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum.
  • the crude product (500 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and MeCN (5.0% MeCN up to 26.0% in 10 min, up to 95.0% in 2 min, down to 5.0% in 2 min); Detector, Waters2545 UvDector 254&220 nm. This resulted in 122.9 mg (32%) of 2-amino-4-([2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]methoxy)pyridine-3-carbaldehyde as a yellow solid.
  • Prep-HPLC-010 Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm
  • mobile phase water with 0.05% TFA and MeCN (5.0% MeCN up to 26.0% in 10 min, up to 95.0% in 2
  • GBT1006 4-((2-(i-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-(methylamino)nicotinaldehyde
  • Step 1 Into a 100-mL round-bottom flask, was placed a solution of tert-butyl N-(4-chloropyridin-2-yl)carbamate (3.0 g, 13.12 mmol, 1.00 equiv) in tetrahydrofuran (50 mL). This was followed by the addition of sodium hydride (631 mg, 26.29 mmol, 1.20 equiv) at 0° C. The mixture was stirred for 20 min at 0° C. To this was added iodomethane (2.24 g, 15.78 mmol, 1.20 equiv) dropwise with stirring. The resulting solution was stirred for 6 h at room temperature.
  • Step 2 Into a 100-mL three neck round-bottom flask, was placed a solution of tert-butyl N-(4-chloropyridin-2-yl)-N-methylcarbamate (1.5 g, 6.18 mmol, 1.00 equiv) in tetrahydrofuran (50 mL). This was followed by the addition of BuLi (2.5M) (3.0 mL, 1.20 equiv) dropwise with stirring at ⁇ 78° C. The mixture was stirred for 30 mins at ⁇ 78° C. To this was added N,N-dimethylformamide (1.5 mL, 3.00 equiv) dropwise with stirring at ⁇ 78° C.
  • BuLi (2.5M) 3.0 mL, 1.20 equiv
  • Steps 3 &4 Into a 100-mL round-bottom flask, was placed a solution of [2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]methanol (1.15 g, 5.29 mmol, 1.00 equiv) in N,N-dimethylformamide (40 mL). This was followed by the addition of sodium hydride (530 mg, 13.25 mmol, 2.50 equiv, 60%) at 0° C. The mixture was stirred for 15 min at 0° C. To this was added 4-chloro-2-(methylamino)pyridine-3-carbaldehyde (900 mg, 5.28 mmol, 1.00 equiv).
  • GBT1007 2-(4-(hydroxymethyl)-1,3-dioxolan-2-yl)-3-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)phenol
  • the phases were separated and the aqueous phase was extracted with ethyl acetate (2 ⁇ 50 ml).
  • the combined organic phases were washed with water (50 ml) and a saturated aqueous sodium chloride solution (50 ml), and dried over sodium sulfate.
  • Step 2 To a solution of (S)-1-benzyl-5-(hydroxymethyl)pyrrolidin-2-one (170 mg, 0.83 mmol) and 2,6-dihydroxybenzaldehyde (0.15 g, 1.08 mmol) in THF (6 mL) was added PPh3 (polymer supported, 1.0 g, 1.25 mmol) and DIAD (0.24 mL, 1.25 mmol) at 0° C.
  • PPh3 polymer supported, 1.0 g, 1.25 mmol
  • DIAD 0.24 mL, 1.25 mmol
  • Step 1 To a solution of (S)-benzyl 2-amino-3-hydroxypropanoate hydrochloride (5 g, 21.58 mmol) in THF-water (1/1, 80 mL) was added K 2 CO 3 (8.95 g, 64.74 mmol) and chloroacetyl chloride (2.92 mL, 36.69 mmol). After stirred for 1 h, it was diluted with EtOAc, organic layer was washed with water, brine, dried and concentrated to give benzyl (2-chloroacetyl)-L-serinate (5 g).
  • Step 2 A solution of (S)-benzyl 2-(2-chloroacetamido)-3-hydroxypropanoate (2.55 g, 9.39 mmol) in iPrOH (20 mL) was added to KOtBu (3.16 g, 28.17 mmol) in iPrOH (15 mL) at room temperature. After stirred at room temperature for 1 h, the mixture was quenched with 6N HCl (10 mL) at 0° C., extracted with EtOAc, organic layers were combined, washed with brine, dried and concentrated to give isopropyl (2-chloroacetyl)-L-serinate as crude product.
  • Step 4 To a suspension of (R)-5-(hydroxymethyl)morpholin-3-one (100 mg, 2 mmol) and 3-iodopyridine (0.57 g, 2.8 mmol) in Dioxane (4 mL) was added CuI (0.08 g, 0.4 mmol), N,N-dimethylethylenediamine (0.05 mL, 0.4 mmol), K 3 PO 4 (0.85 g, 4 mmol). After heating at 100° C.
  • Step 5 To a solution of (S)-5-(hydroxymethyl)-1-(pyridin-3-yl)pyrrolidin-2-one (55 mg, 0.29 mmol) and 2,6-dihydroxybenzaldehyde (0.05 g, 0.38 mmol) in THF (2 mL) was added PPh 3 (polymer supported, 367 mg, 0.44 mmol) and DIAD (0.09 mL, 0.44 mmol) at 0° C.
  • PPh 3 polymer supported, 367 mg, 0.44 mmol
  • DIAD 0.09 mL, 0.44 mmol
  • GBT1123 tert-butyl (2-formyl-3-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)phenyl)carbamate
  • Step 1 tert-Butyl(3-methoxyphenyl)carbamate (0.517 g, 2.3 mmol) was dissolved in dry diethyl ether (12 ml) and cooled to ⁇ 40° C. in a solvent bath.
  • t-Butyl lithium (4.1 ml of a 1.7 M pentane solution, 6.95 mmol) was added dropwise, the reaction was allowed to warm to ⁇ 20° C. and stirred for 2 h more.
  • the reaction was cooled to ⁇ 78° C., DMF (0.54 ml, 6.95 mmol) was added, and the reaction was allowed to gradually warm to 25° C. over 16 h.
  • Step 2 tert-Butyl (2-formyl-3-methoxyphenyl)carbamate (0.38 g, 1.5 mmol) was dissolved in dichloromethane (10 ml) and added dropwise to a solution of aluminum chloride (1 g, 7.56 mmol) in dichloromethane (15 ml) while stirring in an ice bath. The yellowish solution was then stirred in a heat block at 50° C. After 4 h, ice and water were added and the mixture stirred for 15 m. The reaction mixture was extracted with dichloromethane (3 ⁇ 50 ml), the combined organic phases were washed with water (30 ml) and a saturated aqueous sodium chloride solution (30 ml), and dried over sodium sulfate. After evaporation the crude residue was carried directly into the next step. MS (ESI) m/z 138 [M+H] + .
  • Step 3 2-Amino-6-hydroxybenzaldehyde (0.207 g, 1.5 mmol) was dissolved in THF (4 ml). Di-tert-butyldicarbonate (0.726 g, 3.3 mmol) and 4-dimethylaminopyridine (37 mg, 0.3 mmol) were added and the reaction was stirred for 18 h. The solution was evaporated and the residue was purified by silica gel chromatography (0-40% ethyl acetate/hexanes) to give 50 mg (14%) of tert-butyl (2-formyl-3-hydroxyphenyl)carbamate. MS (ESI) m/z 238 [M+H] + .
  • Step 4 tert-Butyl (2-formyl-3-hydroxyphenyl)carbamate (50 mg, 0.21 mmol) and 3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-1-ium chloride (57 mg, 0.21 mmol) were dissolved in DMF (3 ml). The solution was purged with Ar gas. Potassium carbonate (116 mg 0.84 mmol) was added and the reaction mixture was stirred in a 60° C. heat block for 18 h. The reaction was cooled and water (50 ml) and ethyl acetate (50 ml) were added.
  • GBT1131 (S)-2-hydroxy-6-((6-oxo-1-phenylpiperidin-2-yl)methoxy)benzaldehyde
  • Step 1 To a suspension of (S)-6-oxopiperidine-2-carboxylic acid (1.0 g, 6.99 mmol) in EtOH (4 mL) at 0° C. was added SOCl 2 (0.61 mL, 8.39 mmol). After stirred at room temperature for 3 h, it was concentrated to remove all solvents, dried under high vacuum to give corresponding ethyl ester. The ester was dissolved in EtOH (15 mL) and was added NaBH 4 (300 mg) at 0° C., the mixture was warmed up to room temperature and stirred for additional 15 h. The mixture was quenched with Sat.
  • Step 2 To a suspension of (S)-6-(hydroxymethyl)piperidin-2-one (150 mg, 1.16 mmol) and iodobenzene (0.35 g, 1.74 mmol) in Dioxane (2 mL) was added CuI (0.09 g, 0.46 mmol). N,N-dimethylethylenediamine (0.04 mL, 0.35 mmol), K 3 PO 4 (0.49 g, 2.32 mmol). After heating at 100° C.
  • Step 3 To a solution of (S)-6-(hydroxymethyl)-1-phenylpiperidin-2-one (85 mg, 0.44 mmol) and 2,6-dihydroxybenzaldehyde (0.08 g, 0.57 mmol) in THF (5 mL) was added PPh3 (polymer supported, 550 mg, 0.66 mmol) and DIAD (0.13 mL, 0.66 mmol) at 0° C.
  • GBT1717 6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2,3-dimethoxybenzaldehyde
  • the compound was prepared by O-alkylation of 6-hydroxy-2,3-dimethoxybenzaldehyde (A) and 3-(chloromethyl)-2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridine hydrochloride salt (INT-2) according to scheme 9, reaction step 4.
  • the product as white solid was obtained after flash column purification.
  • Step 2 To a solution of 2-(3,4-dimethoxyphenoxy)tetrahydro-2H-pyran (1.0 g, 4.2 mmol) in THF (6 mL) at 0° C. was added TMEDA (0.72 mL, 4.83 mmol) and BuLi (2.5 M, 2.02 mL, 5.05 mmol). After stirred for 1.5 h at 0° C., it was added DMF (1.3 mL). After stirred for 1 h, the mixture was added 6N HCl (4 mL), and was stirred for 1 h at ambient temperature, additional 12N HCl (2 mL) was added to drive the reaction to completion.
  • TMEDA 0.72 mL, 4.83 mmol
  • BuLi 2.5 M, 2.02 mL, 5.05 mmol
  • GBT1718 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-3-methoxybenzaldehyde
  • GBT001723 2-((6-((2-(dimethylamino)ethyl)(methyl)amino)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-6-hydroxybenzaldehyde
  • the compound was prepared by Mitsunobu coupling of (6-((2-(dimethylamino)ethyl)(methyl)amino)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol (A) with 2,6-dihydroxybenzaldehyde (INT-3) according to scheme 9, reaction step 3.
  • INT-3 2,6-dihydroxybenzaldehyde
  • Step 1 Into a 25-mL round-bottom flask, was placed a solution of methyl 6-bromo-2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridine-3-carboxylate (1.3 g, 4.01 mmol, 1.00 equiv) in tetrahydrofuran (15 mL). DIPEA (1.55 g, 3.00 equiv) and [2-(dimethylamino)ethyl](methyl)amine (2.4 g, 23.49 mmol, 5.00 equiv) were added to the reaction mixture. The resulting solution was heated to reflux for 24 hr, and then it was quenched with 30 mL of water.
  • Step 2 Into a 100-mL round-bottom flask, was placed a solution of methyl 6-[[2-(dimethylamino)ethyl](methyl)amino]-2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridine-3-carboxylate (1.2 g, 3.47 mmol, 1.00 equiv) in tetrahydrofuran (20 mL). This was followed by the addition of LAH (330 mg, 8.70 mmol, 2.50 equiv), in portions at 0° C. The resulting solution was stirred for 4 h at room temperature.
  • LAH 330 mg, 8.70 mmol, 2.50 equiv
  • Table 1 includes compounds described below or tautomers or pharmaceutically acceptable salts thereof:
  • the compound is selected from 5-hydroxy-2-(2-methoxyethoxy)isonicotinaldehyde (Compound 218), 5-hydroxy-2-(2-methoxyethoxy)nicotinaldehyde (Compound 219), 5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-oxo-1,2-dihydropyridine-4-carbaldehyde (Compound 220), 5-((2-(4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-oxo-1,2-dihydropyridine-4-carbaldehyde (Compound 221), or a tautomer or pharmaceutically acceptable salt thereof.

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